S228: ACTIVATED SUMOYLATION RESTRICTS MHC CLASS I ANTIGEN PRESENTATION TO CONFER IMMUNE EVASION IN LYMPHOMA
Authors: U. M. Demel, M. Böger, S. Yousefian, C. Grunert, P. Hotz, S. Haas, S. Müller, M. Wirth, M. Schick, U. Keller
Journal: HemaSphere (2022)

Background: During the last decade, the implementation of immunotherapies has revolutionized cancer treatment. However, despite the striking success, often only subgroups of patients respond, and loss of the MHC-I antigen presentation machinery (APM) has been identified as a frequent cause of primary and acquired resistance to immunotherapies. Thus, strategies to restore these pathways may enhance the efficacy of immunotherapies. The post-translational protein modification SUMOylation (SUMO) is a crucial regulatory mechanism in the cellular stress response. Activated SUMOylation is regarded as a hallmark of aggressive cancers. Notably, a selective small molecule inhibitor of SUMOylation (SUMOi), subasumstat, is currently tested in clinical trials. Aims: We aimed to identify the implications of activated SUMOylation for lymphoma immune evasion, and to develop a pharmacological intervention strategy to improve cancer immunotherapies. Methods: A multi-OMICs approach was used to interrogate SUMO-driven immune evasion mechanisms in lymphoma. In vitro findings were informed by in vivo studies in lymphoma xenograft models and syngeneic murine tumor models. Single-cell RNA sequencing (CITE-seq) was applied to decipher in vivo SUMOi-driven changes in blood and immune cell subsets. Results: Starting from a targeted screening for SUMO-regulated immune evasion mechanisms, we identified an evolutionarily conserved pathway of MYC-induced SUMOylation, which attenuated the immunogenicity of lymphoma cells. While activated SUMOylation repressed the MHC-I antigen processing and presentation machinery (APM) and enabled lymphoma cells to evade CD8+ T-cell immunosurveillance, pharmacological inhibition of SUMOylation restored T-cell mediated tumor killing. Importantly, SUMOi amplified the activation of the STAT1 pathway in response to IFNg, which is one of the key regulators of cytokine-induced MHC-I expression. Beyond this, we identified a previously unknown mechanism of SUMO-mediated basal repression of MHC-I and established SAFB, a repressor of immune regulators, as a SUMO-regulated mediator of MHC-I suppression that mechanistically links SUMOylation to MHC-I repression. We thus showed that activated SUMOylation converted lymphoma cells into a less immunogenic state that was restored by pharmacological SUMO inhibition, enhancing the susceptibility of lymphoma cells to CD8+ T-cell mediated killing. Moreover, we revealed that activated SUMOylation was associated with lower abundance and activity of tumor-infiltrating T-cells in vivo, proposing SUMOi as a novel therapeutic strategy to enhance efficacy of immunotherapies. Moreover, by means of single cell RNA-seq analysis we accounted SUMOi with a key function in altering the global immune landscape. Summary/Conclusion: In summary, we show that activated SUMOylation allows tumor cells to evade anti-tumor immunosurveillance and establish SUMOi as rational therapeutic strategy for enhancing the efficacy of immunotherapies in lymphoma and other aggressive cancers.